1. Field of the Invention
This invention generally relates to a coating containing a drug on a balloon device.
2. Description of the Background
Percutaneous coronary intervention (PCI) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the radial, brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress the atherosclerotic plaque of the lesion to remodel the lumen wall. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient's vasculature.
Problems associated with the above procedure include formation of intimal flaps or torn arterial linings which can collapse and occlude the blood conduit after the balloon is deflated. Moreover, thrombosis and restenosis of the artery may develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of the arterial lining and to reduce the chance of thrombosis or restenosis, a stent is implanted in the artery to keep the artery open. Drug delivery stents have reduced the incidence of in-stent restenosis (ISR) after PCI (see, e.g., Serruys, P. W., et al., J. Am. Coll. Cardiol. 39:393-399 (2002)), which has plagued interventional cardiology for more than a decade. However, a few challenges remain in the art of drug delivery stents. A significant concern with respect to stenting is late stent thrombosis for drug eluting stents. The incidence appears to be higher for drug delivery stents than the corresponding bare metal stents (BMSs). Potential causes for this phenomenon are: (1) reduced or delayed healing due to the presence of the anti-proliferative drug, and (2) a chronic inflammatory or hypersensitivity response to the polymeric coating on a drug delivery stent.
An alternative currently being pursued is a drug coated balloon (DCB) onto which is crimped a bare metal stent. Such a system provides a burst release of the majority of the drug and has no permanent polymer, and hence any concern over the polymer is removed. Issues with this approach include drug loss from abrasion and delivery of the crimped/folded stent/balloon to the lesion and drug loss by hydration and diffusion from the drug coated balloon during transit from the RHV (rotating hemostasic valve) to the lesion.
A drug coated balloon may also be used separately to treat a lesion. After treatment a stent may optionally be placed. In this case, no stent is present on the balloon with the advantage of increased drug coated balloon area to transfer drug to tissue. While this alleviates any concerns with drug or coating loss from stent crimping and assembly operations, it leaves the balloon coating more unprotected during the system delivery through the RHV, through tortuous anatomy, or through previously deployed stents.
There are many schemes to place a drug onto a balloon. The simplest is to coat the pure drug. Another simple approach is Scheller's scheme, which is to coat the drug with a binder of Ultravist non-ionic contrast agent. These sorts of coatings certainly release the drug rapidly upon exposure to the aqueous environment. However, we would not expect them to be particularly abrasion resistant, or to have good mechanical properties. Abrasion resistance comes into play when the stent is crimped on and when subjected to the rigors of device delivery. If the mechanical properties are poor with regards to adhesion and ultimate elongation, then the coating will crack and displace when the balloon is expanded. It does minimal good if, when expanded; the coating immediately sloughs off and washes distally.
Another approach is to use a balloon coating similar to what is utilized current for drug eluting stents. These coatings are biocompatible, and if they could maintain mechanical integrity on an expanded balloon, they would be viable candidates. The main problem is that they don't release the drug quickly enough. These coatings are designed to release the drug over a timeframe of weeks to months. Consequently, they are hydrophobic, have low water absorption, and have only moderate diffusivity to the drug. They release only a small fraction of the drug during a 30-60 second balloon inflation.
As the water the absorption of a coating greatly accelerates drug release, the drug may be combined with a water soluble binder. This can serve to enhance the mechanical properties compared to a coating of pure drug, and assist with dissolution of the drug into solution and removal from the hydrophobic balloon. Water soluble polymers absorb water quickly and as the DCB is resident for such a short time, rapid release of drug in minutes is desirable. Most water soluble polymers are water soluble by virtue of hydrogen bonding, or the presence of polar groups. This behavior often results in a high Tg for these polymers when dry. This property in turn makes the polymers brittle when dry. A summary of the Tgs for some common water soluble polymers are shown in Table 1.
PolymerT (° C.)Poly(vinyl pyrrolidone)165Poly(2-hydroxyethylmethacrylate)85Poly(vinylpyrrolidone-co-106vinyl acetate)Poly(methacrylic acid)228Pluronics (PEO-PPO-PEO)variesPoly(vinyl alcohol)85Poly(ethylene glycol)−41
Brittleness is a problem as during the steps of balloon folding, pressing and stent crimping the coating can crack and fall off. PEG coatings are waxy, have mediocre mechanical properties, and actually have stability issues when exposed to ETO or e-beam sterilization as the polymer oxidizes. One solution for brittleness is to plasticize the water soluble coating in order to lower the Tg. Examples of such plasticizers are glycerol, propylene glycol, and poly(ethylene glycol). This is a viable solution. The mechanical properties of the coating can be quite good. However, there are issues associated with added plasticizers which can lead to undesirable results. For example, coating plasticizer may migrate into the balloon, or other components of the delivery system. Also, if ETO sterilization is utilized, the plasticizer can be partially removed during vacuum ETO degassing, and reaction of the plasticizer with ETO can also be problematic as plasticizers with reactive groups can be ethoxylated and such plasticizers can interact with the drug during sterilization. One would next be concerned over any embolic hazards generated by the rapidly dissolving coating.
A possible approach is to use a permanent polymer coating. Such a coating would not generate any embolic hazard and would protect the drug from abrasion during crimping and system delivery. However, the hydrophobic durable coating simply don't release fast enough, and the water soluble coatings have other issues. Another possibility is to use a coating which is composed of water soluble polymer, but it is crosslinked so that it cannot dissolve. This is a viable option if certain problems were addressed. One problem is carrying out the crosslinking reaction in the presence of the drug. Olimus drugs are fairly sensitive. Crosslinking by thermoset processes which react hydroxyl groups, or UV crosslinking via unsaturation, can both potentially react with olimus drugs, as olimus drugs possess both hydroxyl groups and unsaturation. It is possible that very selective and mild cross-linking chemistries exist which could be done in the presence of an olimus drug, but that is a separate challenge. For example, physical or thermal crosslinking via hydrophilic silk elastin like polymers may allow for a burst release of drug.
Another proposed solution is to use solvent soluble thermoplastic polymers to form a coating on a DCB, but the requirements of rapid drug release combined with good mechanical integrity, both wet and dry, excludes many of these polymers. In addition, the requirement for good mechanical integrity becomes even more challenging when utilizing high drug to polymer ratios to encourage the drug to release quickly. For example, the acrylate family of polymers is broad and versatile. However, the more common hydrophobic members of the acrylate family would not work as a balloon coating. Poly(methyl methacrylate) and poly(ethyl methacrylate) are too brittle and would release the drug too slowly. Poly(n-butyl methacrylate) (PBMA) has a Tg in the range of 20-25° C. (depending on molecular weight), and consequently, is flexible enough to accommodate balloon folding but would still release the drug too slowly as it is hydrophobic with a water absorption of only about 0.4% (see, e.g., Aslamazova et al., Polymer Science USSR, 25(6):1484-1490 (1983)). To increase the drug permeability, an approach would be to lower the Tg further by, e.g., the use of poly(n-hexyl methacrylate) or poly(lauryl methacrylate). The limitations with this approach are (1) that while the drug permeability increases, the materials become very soft and tacky, rendering them not suitable for coating a balloon and (2) that hexyl or lauryl groups are also hydrophobic and of larger steric hindrance than n-butyl, which may counter the beneficial effect of a lower Tg on increasing the drug permeability. As another example, an approach may be to increase the permeability not by lowering the Tg, but by increasing the water content by the incorporation of a hydrophilic monomer. However, as described above, the typical hydrophilic monomers with hydrogen bonding and highly polar groups greatly increase the Tg to the point where the polymer is brittle when dry.
Therefore, there is a need for a coating for DCB onto which is crimped a bare metal stent that maintains integrity and provides a burst release of the drug upon deployment of the DCB.
The embodiments below address the above identified issues and needs.